Process for the production of diaminoalcohols of the aromatic series



Patented July 7, 1936 PROCESS FOR THE PRODUCTION OF DI- AMINOALCOHOLS OF THE AROMATIC SERIES Gustav Heilner, Berlin-Fichtengrund, Post Friedrichsthal, Germany, assignor to Chemische Fabriken Dr. Joachim Wiernik & Co. Aktiengesellschaft, Berlin-Waidmannslust, Germany No Drawing. Application January 9, 1934, Serial No. 705,969. In Germany January 12, 1933 13 Claims. ((1260-1285) The present invention relates to a process for the production of diaminoalcohols of the aromatic series, of the type:

in which R1 is an aromatic radicle, R2 hydrogen or methyl, R: a dialkylaminoalkyl radicle and R4 hydrogen or a hydrocarbon radicle.

Dibutylaminoethyl chloride Phenylmethylaminopropanol.

For the purpose of producing these diamino alcohols, a second basic group is introduced into monoamlno alcohols of the type:

using for this purpose, the dialkylaminoalkyl halide or the diaJkylaminoalkyl-sulphonic ester,

As is evident from the equation, 2 molecules of the aliphatic-aromatic amino-alcohol must be employed for the reaction, one molecule being converted into the diamino-alcohol, whilst the other is used to combine with hydrochloric acid formed in the reaction. If it be desired to convert the fatty-aromatic amino-alcohol completely into the diamino-alcohol, the reaction is performed in presence of an agent that will combine with acid, for example, in accordance with the m equation:- 6

CH: 15 H-HaO N CHrCHrN(C4He)z Phenyl-[(methyl)-(dibutylaminoethyDlammopropanol. 20

Since the production of the free dialkylaminoalkyl-halide and dialkylaminoalkyl-sulrihom'c esters is attended with certain difliculties, they are preferably employed in the form of their salts. In such case, it is necessary in causing these salts to react with aliphatic-aromatic alcohols, to increase the amount of the acid-fixing agent to such an extent that 1 additional mole- CHr-CH(OH)CHCH3 CH3 7 N/ +ClCHr-CH2--N(C2Hs)2 35 Phenylmethylaminopropsnol Diethylaminoethyl chloride CtHrCH(0H)CH-CHa CsHs-GH(OH)CHOHs 40 CH: OH;

N\ N\ H01 CHr-CH2N(C:H5)2 H Phenyl-[(methyl)-(diethylaminoethylfl- Phenylmethylaminoptopanol 45 aminopropanol hydrochloride.

cule of acid can be released. The process may be illustrated by the following equation:-

OOH:

ethyl))-aminopropane-1-ol furnishes well-defined crystals of the dihydroiodide, having a p-Metho benyl-methylam oothanol Bonzenesulphonate of diethylaminoethyl-hydrochloride 1 CH1CH2N(C:H5): Sodium benzencsulphonate.

p-Methoxy-phenylmethyl-(diethyl-aminoethyl) aminoethanol.

melting point of 166'167 C., and a. diprimary phosphate having a melting point of 167-168 'C. The specific rotation of the dihydroiodide is Phenylaminopropanol hydrochloride hydrochloride.

Diethylaminoethyl-p-toluenesulphonate Phenyl-(diethylaminoethyl) aminopropanol Potassium p-toluenesulphonate The diamino-alcohols prepared from derivatives of phenylamino-propanol in the above manner constitutes valuable medicaments for the treatment of asthma.

EXAMPLE 1 Z-1phenyl-2- (methyl- (diethylaminoethyl) aminoprOpane-l -ol A solution of 165 parts of l-l-phenyl-Z-methylaminopropane-l-ol in 500 parts of benzene is treated with 68 parts of diethylaminoethyl chloride and warmed on the water bath. Phenylmethylaminopropanol chloride separates out. This is filtered oil, the filtrate being freed from benzene in vacuo and the residue fractionated under a high vacuum. In this operation, a small quantity of phenylmethylaminopropanol, that has not taken part in the reaction, passes over in the first place followed by the new base in the form of a colorless oil.

This has a boiling point under 0.5 to 1 mm. pressure of about 140 C.

The l- 1 phenyl 2 methyl -(diethylamino- EXAMPLE 2 11-1 -phenyl-2- (methyl- (diethylaminoethyl) aminopropane-I -ol 50 grams of d-1-phenyl-2-methylaminopropane-l-ol and 17.2 grams of the hydrochloride of diethylaminoethyl chloride are heated at -120 C. for 8 hours, air being excluded. The reaction product is trituratecl with ether, the whole is rendered alkaline andthe ethereal solution separated. After expulsion of the ether, the residue is distilled under a high vacuum, whereupon the d-lphenyl-Z- (methyl- (diethylaminoethyl) aminopropane-l-ol passes over as a thick, colorless oil having a boiling point under 0.5-1 mm. pressure of about C. The dihydrochloride of the base forms a hygroscopic crystalline mass.

EXAMPLE 3 Z-I-phenyl-Z- (methyl- (dibutylaminoethyl) -aminopropane-I-ol 16.5 grams of l-1-phenyl-2-methylaminopropane-l-ol and 19.2 grams of dibutylaminoethyl chloride are dissolved in grams of benzene and a solution of 5.6 grams of potassium hydroxide in a three-fold quantity of wat :r is dropped in, accompanied by stirring and heating under reflux. After heating for another hour, the layer of benzene is separated, the benzene is distilled 0113 and the residue fractionated in vacuo. The l-1- phenyl-2 (methyl- (dibutylaminoethyl) -aminopropane-l-ol boils at C. under a vacuum of about 0.5 mm. The base forms a strongly hygroscopic, crystalline dihydrochloride.

EXAMPLE 4 I-(p-methomyphenyl) 2 (methyl-diethylaminoethyl) -amin0ethane-1-ol 181 grams of 1-(p-methoxyphenyl) -1-oxy-2- methylaminoethane, 293 grams of diethylaminoethylbenzenesulphonate hydrochloride, 168 grams of sodium bicarbonate, 1000 grams of benzene and 1000 grams of water are heated under reflux for several hours, assisted by stirring. The benzene layer is then separated, the benzene being distilled off and the residue fractionated in vacuo. The l-(p-methoxyphenyl) 2 -(methyl diethylamino-ethyl) -aminoethane-l-ol boils at about C. under a pressure of 3 mm. The dihydrochlorideis a strongly hygroscopic crystalline mass.

EXAMPLE 5 Racemic-I -phenyZ-2- (diethylaminoethyl) -aminopropane-l-ol 187 grams of racemic-1-phenyl-2-aminopropane-l-ol hydrochloride, 307 grams of diethylaminoethyl-p-toluene sulphonate hydrochloride, 1000 grams of benzene and a. solution of 168 grams of potassium hydroxide in 1 litre of water are heated for several hours in a reflux apparatus,- with active stirring. The benzene layer is then removed, the benzene being distilled off under reduced pressure and the residue subjected to vacuum distillation. The racemic-l-phenyl-Z- (diethylaminoethyl)-aminopropane-1-ol boils at about 140 C. under a pressure of about 0.5 to 1 mm. The dihydroiodide crystallizes well and melts at 176 to 178 C.

' EXAMPLE 6 Racemic 1- phenyl 2 methyl (diethylaminoethyl) -amin0propane-1 -ol 20 grams of racemic-I-phenyI-Z-methylaminopropane-l-ol hydrochloride and 32.5 grams of diethylaminoethyl p-toluene sulphonate hydrochloride are dissolved in water, suffused with benzeneand the whole is heated in a reflux condenser. During the heating, a solution of 16.8 grams of potassium hydroxide in 50 grams of water is introduced by drops. After heating for another hour, the benzene layer is separated, the benzene is distilled oif and the residue is subjected to vacuum distillation. The racemic-l-phenyl-2- methyl-(diethylaminoethyl) -aminopropane-1 ol boils at 132-133 C. under a pressure of about 1 mm. The dihydrochloride is a. snow-white, hygroscopic crystalline mass.

What I claim and desire to secure by Letters Patent of the United States is:

1. A chemical compound consisting of diaminoalcohols of the aromatic series of the type:

in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R2 denotes one of the group consisting of hydrogen and methyl, Ra denotes dialklaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl.

2. The chemical compound phenyl-[(methyl) (diethylaminoethyl) l-aminopropanol of the formula oml-ontonl-on-eni 3. The chemical compound phenyl-[(diethyl- .methyl, R: denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl, which comprises causing non-oxidizing inorganic acid esters of dialkylaminoethylalcohols to react upon aminoalcohols of the aromatic series of the type:

Ri-'CH(OH)'CHR2 in which R1, R2 and R4 have the same significance as indicated.

5. A process for the production of diaminoalcohols of the aromatic series of the type:

R1CH(0H)CHR2 NRa I'M in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R2 denotes one of the group consisting of hydrogen and methyl, R3 denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl which comprises causing non-oxidizing inorganic acid esters of dialkylaminoethylalcohols to react upon 1-phenyl-2-methyl-aminopropane-l-ol (Ephedrin) 6. A process for the production of diaminoalcohols of the aromatic series of the type:

m-omom-on-m l q-R: i. in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R2 denotes one of the group consisting of hydrogen and methyl, R3 denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl, which comprises causing halogen hydracid esters of dialkylaminoethylalcohols to react upon aminoalcohols of the aromatic series of th typ RiCH(0H)CHR,

in which R1, R2 and R4 have the same significance as indicated.

7. A process for the production of diaminoalcohols of the aromatic series of the type:

R1-CH(OH)OH-R:

III-Rs R4 in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R: denotes one of the group consisting of hydrogen and methyl, R3 denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl, which comprises causing hydrogen halide addition salts of non-oxidizing inorganic acid esters of dialkylaminoethylalcohols to react upon aminoalcohols of the aromatic series of the type:

R1-CH(0H)-C|3H-R:

in which R1, R2 and R4 have the same significance as indicated,

8. A process for the production of diaminoalcohols of the aromatic series of the type:

R|CH(OH)(|]HR:

ZIP-Rx R4 in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R2 denotes one of the group consisting of hydrogen and methyl, R3 denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl, which comprises causing hydrogen halide addition salts of halogen hydracid esters of dialkyla'minoethylalcohols to react upon aminoalcohols of the aromatic series of the type:

R4 in which R1, R2 and R1 have the same significance as indicated.

9. A process for the production of diaminoalcohols of the aromatic series of the type:

in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R2 denotes one of the group consisting of hydrogen and methyl, R3 denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl, which comprises causing non-oxidizing inorganic acid esters of dialkylaminoethylalcohols to react in the presence of acid-combining agents upon aminoalcohols of the aromatic series of the type:

R1OH(OH)(IIHR1 I i-H in which R1, R2 and R4 have the same significance as indicated.

10. A process for the production of diaminoalcohols of the aromatic series of the type:

R1CH(OH)(|JH-Ra III-R:

4 in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R2 denotes one of the group consisting of hydrogen and methyl, R3 denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl, which comprises causing hydrogen halide addition salts of non-oxidizing inorganic acid esters of dialkylaminoethylalcohols to react in-the presence of acid-combining agents upon aminoalcohols of the aromatic series of the type:"

III-H R in which R1, R2 and R4 have the same significance as indicated.

11. A process for the production of diaminoalcohols or the aromatic series of the type:

in which R1, R2 and R4 have the same significance as indicated.

12. A process for the production of diaminoalcohols of the aromatic series of the type:

in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R2 denotes one of the group consisting of hydrogen and methyl, R3 denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl, which comprises causing a phenyl sulphonic acid ester of dialkylaminoethylalcohols to react upon aminoalcohols of the aromatic series of the type:

R1CH(OH)CH-R1 I'M it in which R1, R2 and R4 have the same significance as indicated.

, 13. A process for the production of diaminoalcohols of the aromatic series of the type:

rn-omom-cn-m I T-Ra it in which R1 denotes one of the group consisting of phenyl and para methoxy phenyl, R2 denotes one of the group consisting of hydrogen and methyl, R3 denotes dialkylaminoethyl, and R4 denotes one of the group consisting of hydrogen and methyl, which comprises causing hydrogen halide addition salts of phenyl sulphonic acid ester of dialkylaminoethylalcohols to react upon aminoalcohols of the aromatic series of the type:

Rl-cH 0n 3nR1 in which R1, R2 and R4 have the same significance 

